American Epilepsy Society

Vast Majority of Women With Epilepsy Able to Get Pregnant

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The vast majority of women with epilepsy are able to get pregnant, with relatively few issues, new research shows.

“There has been the notion and some evidence in the past that fertility is reduced in women with epilepsy compared with the general population, but what these findings suggest is that 90% of women with epilepsy can get pregnant,” study investigator Andrew G. Herzog, MD, professor and director, Neurology, and Neuroendocrine Unit, Beth Israel Deaconess Medical Center, Wellesley, Massachusetts, told Medscape Medical News

The study was presented here at the American Epilepsy Society (AES) 72nd Annual Meeting 2018.

Registry Data

The researchers used retrospective data from a web-based epilepsy birth control registry. Any woman with epilepsy can complete the online survey and get educational materials on safe and effective contraception.

From this registry, researchers had reproductive data on 978 women aged 18-47 years with epilepsy. This included demographic, epilepsy, anti-epilepsy drug (AED), contraceptive, and reproductive data.

The investigators analyzed three outcomes:

  • Infertility rate: The percentage of women who had unprotected sex but did not achieve pregnancy after 1 year.
  • Impaired fecundity rate: The percentage of women who were infertile or did not carry a pregnancy to live birth, excluding abortions.
  • Live birth rate: The percentage of pregnancies that resulted in live births, excluding abortions.

A total of 411 women attempted to become pregnant. Of this group, 373 had 724 pregnancies resulting in 445 live births.

The mean age at pregnancy was 24.9 years, but women who became pregnant ranged in age from 14 to 44 years.

Some 72.6% of the women had a live birth at first pregnancy and 89.0% had at least one live birth in their first two pregnancies.

Of the 411 women, 38 tried but were unable to become pregnant at the end of 1 year, for an infertility rate of 9.2% (95% CI, 6.7 – 12.4). In contrast, the infertility rate among the general population is 6.4%, as estimated by the Centers for Disease Control and Prevention (CDC).

About 20.7% of the women had impaired fecundity, which included the 38 individuals who were infertile and 46 pregnancies that did not result in a live birth.

Impact of AEDs Unclear

Investigators also examined the potential impact of AEDs on fertility. They compared no AED to monotherapy and polytherapy, and no AED to specific classes of AED, including enzyme-inducing, non-enzyme-inducing, enzyme inhibitory, and glucuronidated drugs.

They found that for women on any AED, the rate of infertility was twice that of those not taking an AED (10.3% vs 4.2%), although the sample sizes in this interim analysis were too small to be statistically significant, said Herzog.

Devon MacEachern, BS, who presented the data at a Platform Session during the meeting, said the study would need more than double the participants in the any AED category for the study to be adequately powered to make meaningful conclusions about the potential impact of AEDs on fertility.

The impaired fecundity rate was also almost two times greater for women on any AED than for those not taking an AED (22.2% vs 13.9%; relative risk [RR], 1.79; 95% CI, 0.94 – 3.11; P = .08).

Comparisons of various individual monotherapies to polytherapy were not significant.

In addition, the live birth rate was similar for women on any AED (73.9%) compared with those not taking an AED (79.1%).

However, when investigators examined the impact of specific drugs on fertility, the analysis showed that women on lamotrigine had a significantly higher live birth rate than their counterparts on valproate (89.1% vs 63.3%; RR, 1.41; 95% CI, 1.05 – 1.88; P = .02).

Physicians have numerous issues to discuss with their female patients with epilepsy during office visits. These include seizure management, safety and risks of individual AEDs, as well as contraception, which is “often not adequately addressed,” said Herzog.

A limitation of the study is that the information was self-reported. Also, the women who completed the registry surveys were younger and better educated than the general population, and minority women were under-represented.

Following MacEachern’s presentation, one delegate asked whether the fertility of the women’s partners may have contributed to fertility failure rates.

The “downfall” of this study, and of a CDC general population study, is that they don’t determine whether the male or female contributed to the infertility, she said.

Good News for Patients

Commenting on the study for Medscape Medical News, session co-chair, Kelly Knupp, MD, Pediatric Neurology and Epilepsy Program, Children’s Hospital Colorado, said the results are “good news” for patients.

“The fear of many teenage girls with epilepsy is that they can’t have babies.”

The higher infertility rate among women with epilepsy uncovered by the study is something “we worry about in terms of what that means in a bigger population and something [physicians] have to be cognizant of.”

However, as information in the database is self-reported, “we have to be a little cautious because it doesn’t represent the entire population,” she said.

Worst Seizures Respond to Fycompa

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AMPA antagonist drug shows mettle in generalized tonic-clonic seizures.

Most patients with generalized tonic-clonic seizures (GTCSs) despite conventional therapy showed major improvement when perampanel (Fycompa) was added to their regimens in a phase III trial, researchers reported here.

Some 31% of patients achieved complete freedom from these extremely debilitating seizures after 17 weeks of treatment and about an equal number had at least a 50% reduction in GTCS frequency in the randomized, placebo-controlled trial, said Jacqueline French, MD, of New York University’s Comprehensive Epilepsy Center in New York City.

The overall responder rate (seizure freedom or 50% or greater reduction in seizure frequency) with perampanel was 64.2%, versus 39.5% in the placebo group (P<0.01), French reported at the American Epilepsy Society’s (AES) annual meeting.

At a press briefing, French said the results were important because many drugs approved for less severe seizures are ineffective for GTCSs and may even worsen them. Perampanel, an antagonist of excitatory glutamate activity through so-called AMPA receptors, is currently approved for treating partial onset seizures.

For the current trial, French and colleagues enrolled 163 patients with idiopathic generalized epilepsy marked by GTCSs that did not respond to currently approved therapies. One patient in the placebo group was excluded from the efficacy analysis.

To be enrolled, patients had to have at least three GTCSs during an 8-week baseline observation period while taking from one to three approved therapies. Patients with vagal nerve stimulator implants were allowed into the study if the device had been used for at least 5 months prior to enrollment.

Individuals with progressive neurological disease, Lennox-Gastaut syndrome, history of recent status epilepticus, or use of rescue benzodiazepines more than twice in the 30 days prior to enrollment were excluded.

Perampanel was started at 2 mg/day and then increased in 2-mg increments to a target of 8 mg/day during a 4-week titration period. The drug was then continued for 13 weeks at either 8 mg/day or at the maximally tolerated dose if lower.

Primary endpoints were the responder rate and the reduction in seizure frequency from the level recorded during the initial 8-week baseline period.

As already noted, the responder analysis clearly favored perampanel. So did the other primary outcome: patients in the perampanel group showed a mean 76.5% reduction in GTCS frequency, compared with 38.4% with placebo (P<0.0001).

Complete seizure freedom was achieved by 30.9% of the perampanel group versus 12.3% of the placebo group (not significant).

A total of 23 patients did not complete the study, including 13 assigned to perampanel and 10 to placebo. Of these, 9 in the perampanel group and five of the placebo group stopped the assigned medication because of treatment-emergent adverse effects. There was no clear difference between treatment assignments in the types of adverse events leading to withdrawal, and rates of serious, severe, and fatal adverse effects were the same in the two arms.

Nonserious adverse events were somewhat more common with perampanel, particularly somnolence, dizziness, fatigue, and irritability.

Overall, French and colleagues indicated that perampanel’s side effect profile was similar to that seen in patients with partial-onset seizures.

Although the current trial tested the drug as an add-on, French said she expected that it would also be effective as monotherapy. However, the FDA is currently not approving drugs as monotherapies without trials specifically testing that use.

She said many in the epilepsy community believe that this policy is wasteful and unnecessary, because there is no reason to believe that, if a drug that reduces seizures in patients not responding to another approved therapy, it wouldn’t be effective as monotherapy.

She pointed out that taking patients off their current therapies — as could be required in a monotherapy trial — can be “catastrophic” for an epilepsy patient.

But without an approved monotherapy indication, neurologists and their patients face a dilemma when it is necessary to replace one drug with another. This situation commonly arises when a young epileptic woman becomes pregnant while taking a known teratogenic drug such as valproate. Switching this patient to a drug that is approved only as an add-on is thus, technically, off-label.

Consequently, she said, the field’s major professional societies — the AES and theInternational League Against Epilepsy — are currently drafting a white paper calling on the FDA to approve drugs as monotherapies on the basis of add-on studies.

In the meantime, perampanel’s manufacturer, Eisai, asked the FDA in August to approve an expanded indication covering adjunctive treatment of GTCSs, mainly on the basis of the current study.